Dr. Larry Kwak, MD, PhD, MD Anderson Cancer Center Interview Date: September 26, 2014

 Dr. Larry Kwak describes his remarkable work to create the very ultimate in personalized myeloma immunotherapy - a vaccine tailored to each myeloma patient's particular genetic signature. He describes how it works: some of the tumor cells are pulled out, purified and then packaged with a protein or immune system stimulant and given back to the patient, making it the first and only truly individualized treatment option. He notes that vaccines are best used when patients have a very low tumor burden and describes how this vaccine is being used in a clinical trial along with T cells and autologous stem cell transplant at MD Anderson.  Learn more about this very unique and exciting advance in myeloma care.    The live mPatient Myeloma Radio podcast with Dr. Larry Kwak, MD, PhD

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. Now, before we get started, I'd like to tell you about the new song competition that we have going called "Songs for Life" to help raise money for myeloma research. Musicians donate inspiring songs and then are voted on by you, the crowd. This has been such a fun project so far, so take a look at songsforlife.org. We've only been into it about a week. We've got 11 songs donated so far and they're really fun, so vote for your favorite songs and tell your musical friends to donate a song for myeloma research. Now, we are very fortunate to have with us today one of the foremost world leaders in myeloma immunotherapy, Dr. Larry Kwak. Welcome, Dr. Kwak!

Dr. Kwak: Hello! I'm glad to be here, Jenny.

Jenny: Well, let me give a little bit of an introduction for you before we get started with our conversation. Dr. Kwak is Chairman of the Department of Lymphoma and Myeloma and Co-Director of the Center for Cancer Immunology Research at the University of Texas, MD Anderson Cancer Center in Houston where he holds the Justin Distinguished Chair in Leukemia research. Dr. Kwak graduated from the six-year combined Bachelor of Science and MD Honors Program in Medical Education from Northwestern University Medical School and earned his PhD in Tumor Cell Biology there as well. He then completed a residency in Internal Medicine and a fellowship in Medical Oncology at Stanford University Medical Center in California. Dr. Kwak served as head of the Vaccine Biology section, Experimental Transplantation and Immunology Branch at the NCI for 12 years. His NCI laboratory is credited with a bench to clinic development of a therapeutic cancer vaccine for B-cell malignancies. This was one of the three positive Phase 3 cancer vaccine clinical trials. His vision is to assemble and lead research teams to integrate basic discoveries from academic labs with translational clinical development of new homegrown therapeutics, like next generation cancer vaccines. Dr. Kwak currently sits on many boards including the editorial board for the Journal of Clinical Oncology, the Cellular, Tissue, and Gene Therapies Advisory Committee for the FDA, and the Scientific Advisory Board for the Lymphoma Research Foundation. Dr. Kwak has co-authored more than 160 articles and book chapters, which have been published in journals such as Science, Lancet, New England Journal of Medicine, and Nature Medicine. In May of 2010, he was named to the "Time 100", Time Magazine's list of the world's hundred most influential people. He's a committed physician, scientist and mentor, and lives in Houston with his wife and their four kids. Welcome again! We're so excited to have you on because immunotherapy is such an exciting area for myeloma.

Dr. Kwak: Yes, Jenny, it's really an exciting time for immunotherapy for many different kinds of cancers, but blood cancers in particular, I've always felt, are the disease model where immunologic therapies would first work and maybe would best work.

Jenny: Well, maybe we'd like to start by just giving us a history of your work in cancer vaccines. I know it was deep because that award says a lot.

Dr. Kwak: Well, thank you. Yes, I actually trace my interest, my personal interest, in harnessing the immune system to fight cancer back to a research laboratory experience I had as a high school student. One of my supervisors at the time was a pathologist and he really took me under his wing. After my duties were done each day, he would take me for another hour or so afterwards into his office and show me slides under the microscope of cancer tissues and would point out the immune system cells that were there in small numbers. It really sparked my curiosity as to why those immune system cells would be in a cancer, ultimately to the idea of whether the immune system could in fact be harnessed to fight cancer one day. And that whole experience, although the idea was not new, it was really the beginning of that field 20 or 30 years ago. That really sparked my interest in wanting to become a dual physician and scientist, making discoveries in the laboratory, and then being able to take them myself into the clinic and offer them as new options to patients.

Jenny: What a great experience at that time of your life. I wish my kids would have that kind of experience.

Dr. Kwak: Well, I still do take a number – I’m very active in taking high school and college students into my laboratory in the summers because I think it's really important to have a mentor who will invest the time and effort and because I might be training the next cancer researcher who finds the cure to myeloma.

Jenny: Excellent. Can you describe what you were able to do in follicular lymphoma?

Dr. Kwak: Sure. We started off in follicular lymphoma, as you indicated, and that was for a number of reasons. The targets in lymphoma were just beginning to be developed. This is now 20 years ago when I began this work at Stanford and then eventually moved it to the National Cancer Institute. We had a well-defined target on lymphoma cells, and just like a tetanus vaccine requires a part of the tetanus bacteria, a cancer vaccine also requires a part of the cancer cell. In the case of cancer though, it has to be a really well-defined target molecule because 99% of the proteins that are expressed by cancer cells, as you may know, are also expressed by normal cells. And so, for us to have a window to be able to specifically attack the cancer cell, we have to identify a protein target, which is really almost exclusively expressed by the cancer cell. This particular target, we were able to isolate and purify in enough quantity that we could actually formulate it into a vaccine. We initially did these studies in mouse models of lymphoma. The purpose of those studies, which was very important, was to first establish the concept that a vaccine could work as a therapy, so this is different from a traditional infectious disease vaccine like a tetanus vaccine where you're giving it in the prevention setting. As you know, these vaccines are designed to actually fight cancer, which is already established, and that's a much more difficult task, but we're able to show that -- in fact, the early results in animal models were in fact negative. They mimic the challenge that we would eventually have in human cancer patients and clinical trials, but what we found we had to do in mouse models was to package the target protein in such a way that the immune system would recognize it as a foreign protein. And so, there are several immunologic tricks as it were that we were able to optimize. One was coupling the protein to a large carrier protein which itself makes the smaller tumor protein look more visible to the immune system. The other was to combine it with an immunologic adjuvant. An adjuvant is a substance which nonspecifically stimulates the immune system. And so, combining these two things, we were able to show that the vaccine had the desired effect in mouse models importantly that the vaccine could elicit T-cells, which were specific against the tumor. That was actually a first because most of the cancer vaccine is being developed at that time to elicit an antibody response. We really think that T-cells are the most effective against fighting cancer, and in particular in myeloma, which I can explain a little later. Those trials, those tests in animal models looked promising, so I got the privilege at the National Cancer Institute to move these into first in-human clinical trials. Over the course of about ten years, we progressed through Phase 1 and Phase 2, and ultimately because of the positive results, to a Phase 3 randomized controlled trial, which was completed as you indicated about three years ago. That particular product for lymphoma is undergoing review by the European FDA right now. And so, our hope is that it will be available for lymphoma patients sometime in the next 6 to 12 months. Now, you asked me about myeloma and again, going back 10 or 15 years, what we found was that the same target that we had found for lymphoma cells was actually also expressed most likely in multiple myeloma cells. And so, the trials and experience in lymphoma now paved the way for doing similar studies and testing similar vaccines in multiple myeloma. I should add it's an exciting time for immunotherapy in myeloma because in addition to this target antigen that we've been working on for a long time, there are now several other candidate tumor proteins in multiple myeloma which are being exploited for vaccine development by other groups around the country.

Jenny: Amazing! Now, just to go back a little bit -- well, maybe you should just keep explaining a little more about myeloma. You said we were going to go back and talk a little bit about what the T-cells do. I guess in general as an overview, you pull the cancer cells out. You purify them in some way. You package them with a target protein or an adjuvant, and then you give it back to the patient. Is that the overall process? Is that what I'm hearing you say?

Dr. Kwak: That's an accurate description of the strategy, yes. Because this tumor protein is specific for each patient's lymphoma or myeloma, meaning that it's sort of a molecular signature that's unique to each patient's tumor, we have to do this process that you just outlined for each patient. If we have two patients with multiple myeloma, their molecular signature is going to be slightly different. And so, we have to make separate vaccines, individualized vaccines for each patient. This is really an ultimate personalized therapy. There's a lot of talk these days about personalized medicine and this is really a very good example of a personalized therapy where we custom-make the vaccine for each patient that comes along.

Jenny: Okay. That stimulates a lot of other questions. How do you go about doing that and how long does it take? This is not just a drug that you're developing and giving to everybody in the same way. This is very personalized, which is completely remarkable.

Dr. Kwak: Yes. It's a little bit ahead of its time and it's been a little bit slow to develop from a commercialization standpoint because companies, biotech companies and pharmaceutical companies don't have a really good business model yet for personalized therapies. I can maybe think of one example in cancer of a truly personalized therapy. As you may know, the pharmaceutical industry, they're accustomed to the model of one drug on the shelf for many people. This would be one drug for one person, so again, it's been a little slow to catch on from a commercialization standpoint; to continue to move it forward, most of the progress has been made still in the academic sector, our group as well as other groups working in this field. I think it points to the importance of supporting research for nonprofits and academic research institutions because this is a very good example of something that would not be moved forward. It is not being moved forward on its own by the pharmaceutical industry just yet. I think if we have a few more successes, then it will catch their attention and we can count on the full power of the pharmaceutical development industry to move it forward.

Jenny: In general, how long would it take to make a particular vaccine for a particular patient?

Dr. Kwak: Right now, to make a myeloma vaccine, it takes about -- the actual production process takes about a week, but the release, it takes an additional two or three weeks to test the product for sterility and safety before it can be released for use. Start to finish, it's about one month is how long it takes.

Jenny: And then how do you determine dosage for something like that when you're doing this on a personalized basis?

Dr. Kwak: That's a good question. The drug, if you will, is personalized. Everything else is standardized though, so the dose is based on a set or fixed dose. The route of immunization is under the skin and this is all taking advantage of our experience in lymphoma patients.

Jenny: It sounds like you can modify it, but there are some parts to it that are standardized. Now, let me go back to one of the questions that you said. You said that there's a target that you've been hitting in lymphoma that applies similarly to myeloma and that there are additional targets in myeloma that might be really good candidates, so what is the target that you are hitting? And then I'll ask some follow-up questions about myeloma genetics.

Dr. Kwak: Sure. The target that we've been focused on is called the B-cell receptor. It's the surface receptor protein, antigen receptor protein, that's present in all myeloma cells. This is the protein that has a unique signature that varies from patient to patient. Now, I should add, the reason that there is a key difference between lymphoma and multiple myeloma, of course, there are different diseases with different natural histories and different responses to treatment, but this particular receptor protein is present in lymphoma cells on the surface of the cell, whereas in myeloma cells, it's present internally. This is also what's referred to -- most patients will know this as the M protein. This is the target protein. So the M protein in multiple myeloma cells is internal and then it's secreted obviously out into the bloodstream, but for us to be able to successfully have the immune system recognize it is a little bit of a challenge in myeloma that we don't have in lymphoma because the protein is internal to the cell. And so, it's not visible on the external surface of the cell. But T-cells -- and this is why T-cells are important especially in multiple myeloma -- their specialty is actually seeing proteins that are on the inside of the cell. It's a little bit complicated to explain, but eventually those internal proteins, pieces of those internal proteins do get put on the surface of the myeloma cell where they can become visible then to T-cells, but would be invisible to antibodies. That's why it's important to have a vaccine which particularly stimulates T-cells, and T-cell therapies would also be expected to work very well against this particular target.

Jenny: So are you saying that T-cells can only recognize the protein if it's on the surface and they can't recognize it unless something else pulls it out? Is that accurate?

Dr. Kwak: That's correct, yes. That's correct.

Jenny: And then when you talk about how T-cells work, we've done some other interviews with people doing research in CAR T-cells. What's the difference? Is that the same thing?

Dr. Kwak: That's a very good question. There is a lot of publicity and very really exciting responses being seen in clinical trials of CAR T-cells. What a CAR T-cell is, it's a T-cell that's actually been taken out of the patient's body and engineered to express this particular receptor, and then put back into the patient. That's different from a cancer vaccine in which everything is happening inside the patient with its own native immune response, so it's very much again like a tetanus vaccine where you get a shot and what it does is it activates the immune system. In this case, it activates the T-cells, which are specific for the myeloma cells, and then they go and find the tumor cells and eradicate it on their own without any manipulation outside of the body. There are two alternative and complementary approaches. In fact, one of the clinical trials that we are right in the middle of doing now here at MD Anderson -- Dr. Qazilbash is the principal investigator of this study -- is a combination of clinical trial with the vaccine and CAR T-cells. In this particular clinical trial, patients who sign up are getting a vaccine first to activate the T-cells inside the body, and then they're taken out of the body, engineered, and then put back into the body. There are actually a couple of booster vaccines that are given to further boost those engineered T-cells after they've been put back in the body, so we're trying to capitalize on both approaches. He already has about 20 patients who have enrolled and are being treated on that particular clinical trial.

Jenny: And this is in myeloma or in another blood cancer.

Dr. Kwak: No. It's in multiple myeloma, yes. I should add it's in the setting of stem cell transplantation, autologous stem cell transplantation. The reason for doing this in stem cell transplantation goes all the way back to another principal that we established in lymphoma, which is that the best clinical setting to administer these immune therapies is in the minimal disease setting. In other words, we don't think these cancer vaccines will work very well in a patient who has a lot of tumor onboard. In the case of lymphoma, our strategy was always to get rid of 99% of the tumor cells with standard chemotherapy and then come in with the vaccine afterwards to mop up the residual tumor cells. The same principle now is being applied in multiple myeloma, in this clinical trial in multiple myeloma where it actually takes a stem cell transplant, as you may know, to eradicate most of the disease, most or all of the disease to get to that same minimal disease setting. And then we come in, in this case, with the combined CAR T-cells and a vaccine to mop up the residual tumor cells after the stem cell transplant.

Jenny: It's all afterwards because I've heard of some studies doing a little bit of vaccine before and then a stem cell transplant, and then a little vaccine after, but this is all after?

Dr. Kwak: No, this is both. This is both, so it's both plus the engineered T-cells after the transplant also.

Jenny: From what I've heard about the CAR T-cells is they're very potent and you have to be very careful.

Dr. Kwak: Yes. That, I think, is a complication that we do have -- that's the challenge now, but I'm optimistic we'll figure out how to make them more specific. The last thing that we would want to do is to have any therapy be harmful, but the last thing from the immunotherapy standpoint we would want to have happen is that immunotherapy be thought of as chemotherapy where there's a lot of collateral damage because I think the beauty of harnessing the immune system is the specificity, if we can just learn how to harness it properly. And so, one way to direct the immune response, that angry immune response, is with the CAR T-cells, perhaps would be to combine it as we're doing with cancer vaccines to kind of direct the immune response more against the tumor rather than against collateral cells.

Jenny: It's amazing. I think it's just amazing what's happening. To go back to what you're talking about, in terms of the personalized myeloma vaccine, is that just in the lab is what you're saying? Has it been used in a number of patients? Could someone get that as a therapy if they wanted to?

Dr. Kwak: Yes. I apologize for not being clear. This myeloma vaccine and clinical trial that I just described with Dr. Qazilbash here at MD Anderson is a clinical trial, so it is being actively offered to patients. This clinical trial is also -- it's actually a joint effort between MD Anderson and the University of Pennsylvania, Dr. Carl June and Dr. Stadtmauer's group there, so patients can be enrolled, can have access to this therapy at either place, either in Houston or in Philadelphia.

Jenny: That's just amazing. Unbelievable! It's so exciting to hear about this. I have a question. When it comes down to the different genetics in myeloma, people have t(4;14) translocation or t(11;14) or del(17p). Is the vaccine more or less effective for specific myeloma subtypes in any way?

Dr. Kwak: Well, as we talked about, we're just now starting to test this in patients, so I don't think we have enough experience yet to know about the effectiveness of the vaccine in different subtypes of myeloma. My guess though is that the vaccine should be effective against those different subtypes that you described mainly because none of the targets for the vaccine are affected by those translocations, so it should still be intact regardless of the translocation.

Jenny: So everybody still has the M protein, right?

Dr. Kwak: Yes, that's right.

Jenny: That makes a lot of sense. When you were talking about vaccines that are best to be used with a low tumor burden, I know that there are patients either with smoldering myeloma or patients who are in remission status that may want to be preventative. Dr. Palumbo in his interview, he said even if you're MRD negative, you probably still have myeloma cells lurking around there somewhere. Are you using these vaccines in that way? Can you use them in a clinical trial for someone who wanted to choose that option? I know that's hard to test for, but --

Dr. Kwak: As I indicated, our group is -- or Dr. Qazilbash is testing these vaccines in the minimal disease setting after stem cell transplant. There are other groups that I'm happy to say are taking this forward into, just as you described, this smoldering myeloma setting because that also represents a minimal disease setting or the disease hasn't yet really taken off or taken hold and had a stranglehold on the immune system yet. So there is a clinical trial which is sponsored by a company called OncoPep, which is testing a vaccine in myeloma, in smoldering myeloma patients. They have already tested this in at least ten patients and I know are planning to test it in additional patients, but this particular vaccine is slightly different. It uses a slightly different target. In fact, it uses a mixture. It's a combination of about three or four different targets, which are different from the one that I've been focusing on. And so, I think this kind of approach is extremely promising and it represents another shot on goal if you will for us.

Jenny: Well, the only vaccines that I've heard of so far are just what you talked about earlier, just the over-the-counter pharmaceutical company or in the lab has developed a single vaccine for everybody. This is the first time I've ever heard of it being individualized in myeloma, so congratulations for doing that.

Dr. Kwak: Well, thank you. We've made a lot of progress and it's required some perseverance, but I think we still have a long way to go. I'm really thankful for all the opportunity and the support to be able to continue this research and offer these new options to patients.

Jenny: Well, it's fabulous. Now, I was reading about lenalidomide being used to boost the power of some of the vaccines that you've been working on in lymphoma. Is this now also being tested in myeloma and how does that work? Why would you use that?

Dr. Kwak: Yes. We're personally very excited about lenalidomide as a potential vaccine adjuvant. Our interest in lenalidomide actually came from its potential use as an adjuvant for the vaccine, for the lymphoma vaccine. In fact, lenalidomide, it's a very good vaccine adjuvant because it activates T-cells. And so, many people have thought that this will be an ideal adjuvant particularly for use with a myeloma vaccine, first, because it activates T-cells primarily and secondly, because obviously, lenalidomide has good antitumor activity itself in multiple myeloma. In fact, the company that I just mentioned, OncoPep, is planning their next phase trial with their peptide vaccine in combination with lenalidomide. I don't think that the trial is active just yet, but it should be very soon. So yes, that's definitely an exciting idea that is going to be tested soon in patients.

Jenny: Wonderful! Are there other therapies that might boost the power of the vaccines that you're working with?

Dr. Kwak: Yes. That's also a very active area of research in clinical trials. That's with the availability of this new checkpoint blockade. These are monoclonal antibodies such as anti-CTLA4. It's also known as ipilimumab, which has been approved already for use not in myeloma, but in melanoma, skin cancer, but is also being tested in multiple myeloma alone. There's also an antibody against the PD-1 molecule, so these are all molecules that dampen the immune response, so these antibodies block the dampening of immune response to release the breaks as it were on the immune response. And so, these are two good examples, the ipilimumab and the PD-1 antibodies that are now being tested pretty widespread in most types of cancers. It won't be long after we have the safety data from these antibodies that we'll be able to combine them with other immunotherapies like cancer vaccines and CAR T-cells in diseases like multiple myeloma, so I think those clinical trials will be available -- those combination clinical trials would be available probably within 12 months.

Jenny: Well, let's talk about that for a little bit because it seems like immunotherapy is just exploding with a lot of different kinds. There are the monoclonal antibodies that are the CD38 and the CD8, and the PD-1 blockers and the CAR T-cells. How do you determine which are showing the most promise and how do you weigh that? How should patients weigh that when they go to look at what clinical trail they should join? That's a challenging situation to try to figure out which one do I choose?

Dr. Kwak: Right. It's a good thing and then also a challenging thing because it's like having a smorgasbord of potential options. The field right now needs to methodically test each of these new agents first by themselves because the worst thing we'd want to do is to have undue side effects or toxic effects to make sure these agents individually are safe before testing them in combinations. The combinations then will need to be designed rationally because just as combinations could synergistically have a better effect on the tumor, they could also synergistically have more toxic effects, so my recommendation to patients is to be patient with us. These trials, it may seem to take longer than necessary maybe to become available to the patients, but this kind of groundwork needs to be done before real combinations can be tested and offered to patients, but I'm very optimistic. I think there's a lot of enthusiasm. The full weight of the pharmaceutical industry is behind these products now. And so, I think the progress in academia as well as in industry are working together to make this a reality for patients and I think it's going as quickly and as safely as it possibly can right now.

Jenny: Well, that's a lot to coordinate.

Dr. Kwak: Yes, and it requires a lot of collaboration and working together between academic institutions and industry. I must say I've been very impressed with the degree of collaboration in general between the two, so I think this is going to translate into real progress. For the individual patient right now, of course, your doctor is the best source of up-to-date information. Obviously, the Multiple Myeloma Research Foundation is a great source for up-to-date information also.

Jenny: Now, one myeloma specialist mentioned, when we talk about combinations, they mentioned that myeloma always requires multiple drugs, so you're trying to hit it from all different aspects, either preventative or stimulating different parts of the body to fight it, yet the drugs aren't developed intentionally in combinations, but first as standalone. They test for safety, toxicity, dosing, and then they do it in combination. Are you seeing anything in the vaccines -- and you're obviously using these together, so are you seeing anything in these vaccines and immunotherapies that would encourage more drug combination developments as intentional combinations? Does that make sense?

Dr. Kwak: Yes. That's a rational -- another word to use would be "rational", rational combinations. What we haven't talked about is that there's a large amount of research going on primarily in academic institutions in animal models of multiple myeloma where these kinds of combinations can be tested quickly and rational combinations can be developed. This is how we eventually arrived at the combination that we're testing in the multiple myeloma clinical trial with Dr. Qazilbash now, combining T-cells and vaccine, and vaccine with lenalidomide. Those were first found to be very effective in preclinical animal models of multiple myeloma. And so, a lot of this is behind the scenes and gets published in literature that's not necessarily what patients read, but rest assured it is being done and it's quite active, so I think it does actually influence when drugs have been shown to be safe individually. These kinds of pre-clinical combination testings in animals do actually guide the design of combination of clinical trials.

Jenny: And it would be so nice if we could find existing drugs that could be used together to do what we needed to do in myeloma and it would be much faster, wouldn't it?

Dr. Kwak: Yes, that's right. So we have a lot of drugs now in myeloma, which we didn't have ten years ago. What needs to be worked out is some of these, when combining some of these drugs -- like lenalidomide is a great example because it actually makes sense to combine that with an immune system, an immune therapy, because lenalidomide has positive effects of the immune system. But there are other drugs, for example, Velcade, which probably have a dampening effect on the immune system, so it might not make sense to test them clinically, to test Velcade in combination with immune therapy clinically. That's why these kinds of pre-clinical studies in animal models are very important and the research support that goes for those kinds of studies in academia is really important.

Jenny: What's the phase of this study that we've been talking about, the vaccine plus the T-cell?

Dr. Kwak: It was technically Phase 1. It's a combination of Phase 1 and 2. It's Phase 1 because it's the first time the combination has been tested in human patients; Phase 2 because each of the therapies has individually been tested in patients before.

Jenny: That makes sense and then they're trying it together for the first time.

Dr. Kwak: Right, so we know they're safe individually.

Jenny: Now, let me ask you about a few other papers that I was reading about your work. You were talking about 3-kinase inhibitor, which has a very long name, NVP-BKM120, so I wanted to ask you about that. You had written a paper on something called Dickkopf-1 as a target. Do you want to briefly describe those?

Dr. Kwak: Sure. I think we're slowly coming up with new potential targets in multiple myeloma cells as the genetics get better. We're able to identify more and more candidate proteins, which are made either exclusively by myeloma cells or overexpressed in larger amounts in myeloma cells that would make them potential good targets for immune therapy, either targets of CAR T-cells or targets of vaccines or targets of antibodies, monoclonal antibodies. Dickkopf-1 that's known as DKK1 is a good example of this. This is a target which is expressed to some degree in normal cells, but it's definitely overexpressed in multiple myeloma cells, and so that's why the interest in this is a potential target. What's special about this particular protein is that it's on the surface of the cell, of the myeloma cell. So it means that it can be visible to antibodies, which means that it should be possible to make a monoclonal antibody as a therapy to this target. It also should be possible to make CAR T-cells to the target because it's on the surface, as well as internally, it could be a good target for vaccines. A lot of this work is now being done at the Cleveland Clinic by a group there headed by Dr. Qing Yi. His group is now actively developing all three approaches for this, as well as a related target called beta-2 microglobulin. I know that's a mouthful of words, but --

Jenny: I think that I've heard of that before. Okay. Well, that makes sense. Maybe you can describe a little bit more about your lab and where your work is headed next.

Dr. Kwak: All right. Twenty or 30 years later, I'm still excited every time I get up in the morning to come to work because this could be a day that we make a discovery in the laboratory that could have an impact on patients. It’s what I love about my job. I tell my kids I feel guilty some days for being paid because I love what I do, but just the prospect of being able to move things from the laboratory, from the bench to the bedside, and to have the support to do that is what really spurs me on. This is really what my staff and the laboratory find really stimulating, too. Many of them have been with me for 15 years, almost 20 years because they're just excited to share my excitement about the possibility of moving things from the laboratory to the clinic. What we're doing now is we are getting ready to take -- and this will be of interest to multiple myeloma patients where we've developed a new -- I'll call it a new vaccine platform. It's a new way of delivering the target protein in such a way that the immune system recognizes it as foreign. What we do is the first steps are the same as what we've been talking about, that is, we take the individual patient's tumor cells and we have to isolate the -- in this case, we isolate the actual DNA for that target protein and sequence it. And then we actually knit two pieces of DNA together. The second one is constant and it encodes a special type of cytokine. It's called a chemokine and this fusion DNA is what's injected as the vaccine, so we're actually taking naked DNA and injecting that as a vaccine. We have done extensive testing in animal models of multiple myeloma and have received approval now for a clinical trial, which will probably open in January of this year in Waldenstrom's macroglobulinemia. That, as you may know, is a disease which is very closely related to multiple myeloma. It's basically the equivalent of smoldering myeloma. It's patients who are newly diagnosed with Waldenstrom's macroglobulinemia who have just a very small amount of disease and don't require treatment otherwise. The only other alternative really is toxic chemotherapy. This clinical trial we're very excited about and we're hopeful that it will be open in a few months as I indicated. That's the major effort in our laboratory right now.

Jenny: This is kind of an extension of what you've already done because it's similar and that it's all personalized, right?

Dr. Kwak: Yes, that's right. It's personalized because the target protein, the receptor, the M protein is individualized.

Jenny: And then how long do you think it will be until that is brought into myeloma?

Dr. Kwak: It's really a matter of resources, quite frankly. I think if this initial clinical trial is successful, it will be offered in 12 patients, then I think it will provide the stimulus to take this into the multiple myeloma setting, a very similar setting of smoldering myeloma.

Jenny: Okay. Well, we're so very excited that you're going to work every day, so excited. It's amazing what you're doing.

Dr. Kwak: Well, it's just a real privilege and we've got teams of scientists and colleagues who are just eager to develop new therapies for patients.

Jenny: Now, this whole series was based around the idea that if we had more patients participating in clinical trials that your work could move along faster. Do you have any comments about patients participating in clinical trials or how that affects you in your lab?

Dr. Kwak: I think clinical trials are really important to move the field forward. I think the vast majority of clinical trials also have the potential to benefit individual patients because this is how drugs get developed. If you look at all of the established drugs now, which we take for granted let's say in multiple myeloma, say thalidomide or Velcade, they were all first available only in clinical trials. And so, if you were one of the lucky participants in those early clinical trials of Velcade or lenalidomide, you've got access to a drug which eventually was shown to be highly active. And so, I encourage all of my patients if a clinical trial option is available and if there's any way they can at all participate in a trial that they seriously consider it. I guess I can't state that strongly enough. I think sometimes clinical trials are viewed with skepticism by patients, but in my experience, a clinical trial cannot get to the point where it's actually offered to a patient unless there's some potential benefit to the patient. I think it's always in a patient's best interest to consider a clinical trial.

Jenny: I completely agree, which is why we started this series. I participated in multiple clinical trials. I'm a huge advocate for participation, but it sounds like you also need the resources in order to continue the work so you can have a clinical trial.

Dr. Kwak: Yes, exactly. The challenge that we're faced with in academia now is research funding or the lack of it because the federal government support for cancer research in general has gone down in recent years. There are a lot of good ideas that are not getting tested, including in multiple myeloma.

Jenny: Okay. Well, we'll be participating in that piece and we'll be sharing a little more about that later, but I wanted to open it up and take some time for caller questions. If you have a question for Dr. Kwak, please call 347-637-2631 and press 1 on your keypad.

Caller: Thanks so much, Jenny. Hi, Dr. Kwak! I'm a smoldering multiple myeloma patient, so I'm listening very intently to everything that you have to say because I'm very interested in trying to find a clinical trial that might be a good fit for me. I've been looking at the OncoPep vaccine trial, the one that they're now coupling with Rev, but I've realized that I have to have a particular type of immune system, so I'm getting tested for that to see if this is actually a possibility for me to consider. Also the PD-1s, I think that they hold a lot of promise as well. I'm listening to what you're developing as well, which is really exciting to hear as a smolderer because I think that we may hold the key to really figuring out if this disease can be really stopped in its tracks. With that said, should I hold tight? Should I sit back? Should I just hold tight and see what else is on the horizon, or in your opinion, is it worthwhile now to perhaps pursue one of the ones that exist? I'm speaking particularly about the ones with the immunotherapy because that personally to me is what I'm looking for.

Dr. Kwak: Sure. I think, first of all, you have the luxury of time. This smoldering myeloma situation can go on for a long time, so I would not be quick to jump into a particular therapy. But that said, I think there's very little downside to trying a therapy like the OncoPep vaccine mainly because it should not eliminate any future options for you.

Caller: Right. Dr. Richardson explained that.

Dr. Kwak: Right, and that's very important, and also because it probably will not do harm. I say that because it's a specific vaccine, unlike the PD-1 antibodies which will activate the immune system in general. That's why sometimes you get side effects, unanticipated side effects. So I would be a little more enthusiastic about the OncoPep vaccine in your situation for those reasons, but I think the overarching consideration is that you can afford time to wait or anticipate until we do develop therapies that are clearly effective in the smoldering myeloma setting.

Caller: That's the trick. No one really knows when the switch gets turned. It's a tough situation to be in in that watch and wait. You want to be proactive, but then on the other hand, you don't want to jump the gun, but the OncoPep sounds to me very interesting and again, because Dr. Richardson had also explained that it triggers the T-cells, so even if you do end up progressing and go down the road with the stem cell transplant, they're hoping that maybe that T-cell reaction I guess that you get would somehow be maintained. MD Anderson is also participating in that, aren't they?

Dr. Kwak: I'm not sure. MD Anderson did participate in the first trial, but I'm not sure what the plans are for this, the one with the Revlimid.

Caller: Well, I look forward to hearing about your future ones as well. We'll be keeping an eye on that. Thank you so very much for your time and for what you do.

Dr. Kwak: You're quite welcome.

Caller: Bye now.

Dr. Kwak: Bye now.

Jenny: Thank you for your questions. Our second question, please go ahead with your question.

Caller: Hi! Thanks for taking the call. I have two questions, one for Dr. Kwak and one for Jenny. I'll start with Dr. Kwak first. You have to harvest the stem cells. Let's say you've been through a stem cell transplant and you're in remission. For the particular trial that you're in process with right now, you have to harvest the stem cells prior to your first transplant, so do you have to know that you're going to participate in this trial or could you pick up somebody on the backend of the trial?

Dr. Kwak: That's a good question. At this time, it's only possible to enroll on the trial if you're going into the stem cell transplant because as you indicated, there's an inherent requirement to harvest the actual tumor protein that makes the vaccine. In your situation, of course it's great news. If you're in remission, you don't have the protein there to be able to harvest, but --

Caller: Isn't the point of a vaccine is you take it before you need it?

Dr. Kwak: Yes.

Caller: And myeloma always comes back. If you harvest the stem cells prior to the transplant, those don't count, right? Those aren't going to help you.

Dr. Kwak: That's right.

Caller: You need to actually harvest the tumor.

Dr. Kwak: Right. We need to harvest the tumor, exactly, since it's custom-made. The vaccine is custom made from the tumor cells.

Caller: Okay, understood.

Dr. Kwak: Yeah, but there will be other clinical trials as we discussed that are being tested just like the OncoPep trial that the previous caller asked about where you don't have to harvest -- they're not personalized, so you don't have to harvest the tumor beforehand, and that may be soon a possibility for patients like yourself.

Caller: Okay, and then the question for Jenny is week after week, how do you choose the doctor to come on your show? You were able to identify groundbreaking ideas week after week. Is there that much research really happening in myeloma? I guess there is. My question is how do you come up and select the doctors? How do you get access to these amazing interviews each week?

Jenny: Well, I think there's an amazing pool of doctors that are focusing on myeloma and I think it's so exciting what's been happening in myeloma. Some of it is just research, reading the papers, and finding out -- just looking at the most recent research and then contacting the doctors that are doing that research, to ask about it. A lot is just pure curiosity. Some of it is having patients say, "Hey, I heard about this. Can you call that doctor and ask him if he would be interested in participating," or just because I want to find out more about it." So it's some group help as well, but a lot of it is just -- one thing leads to another and sometimes people will mention each other. Dr. McCarthy mentioned that Dr. Holstein was working on something, and then someone else mentioned that Dr. Kwak is working on something. I reach out and if they're willing to share, they participate, which we totally love.

Caller: Well, this patient to patient support is amazing, and the collaboration with the doctors is unprecedented, so keep up the great work, guys. Thanks for letting us participate.

Jenny: Well, thank you very much for your question.

Dr. Kwak: Thank you.

Jenny: Dr. Kwak, thank you so much for joining us today. We are so thankful for your leadership and your research to move immunotherapy and vaccine forward as quickly as possible for us, so our hearts are just full of gratitude for you.

Dr. Kwak: Well, it's really a privilege to be working in this area and it's really been my pleasure to be on with you today on the show and to be able to communicate some of the enthusiasm that we have right now to patients directly, so thanks for the opportunity.

Jenny: Well, it's wonderful what you're doing, so just keep going.

Dr. Kwak: Okay.

Jenny: All right. Well, thank you everyone for listening to another episode of Innovation in Myeloma. Join us for our next interview as we learn more about how we, as patients, can help drive to a cure for myeloma by joining clinical trials.